Genetic analysis using targeted exome sequencing of 53 Vietnamese children with developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEE) refers to a group of rare and severe neurodevelopmental disorders where genetic etiologies can play a major role. This study aimed to elucidate the genetic etiologies of a cohort of 53 Vietnamese patients with DEE. All patients were classified into known electroclinical syndromes where possible. Exome sequencing (ES) followed by a targeted analysis on 294 DEE-related genes was then performed. Patients with identified causative variants were followed for 6 months to determine the impact of genetic testing on their treatment. The diagnostic yield was 38.0% (20/53), which was significantly higher in the earlier onset group (<12 months) than in the later onset group (≥12 months). The 19 identified variants belonged to 11 genes with various cellular functions. Genes encoding ion channels especially sodium voltage-gated channel were the most frequently involved. Most variants were missense variants and located in key protein functional domains. Four variants were novel and four had been reported previously but in different phenotypes. Within 6 months of further follow-up, treatment changes were applied for six patients based on the identified disease-causing variants, with five patients showing a positive impact. This is the first study in Vietnam to analyze the genetics of DEE. This study confirms the strong involvement of genetic etiologies in DEE, especially early onset DEE. The study also contributes to clarify the genotype-phenotype correlations of DEE and highlights the efficacy of targeted ES in the diagnosis and treatment of DEE.

De novo homozygous variant of the SCN1A gene in a patient with severe Dravet syndrome complicated by acute encephalopathy.

Variants in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and they are generally heterozygous. Here, we report a homozygous missense variant, NM_001165963.4: c.4319C>T (p.Ala1440Val), in the SCN1A gene which seemed to occur de novo together with a gene conversion event. It's highly possible that this variant, although located in a critical functional domain of protein Nav1.1, depending on the nature of the amino acid substitution, may not cause the complete loss of protein function. And the accumulated effect by having this variant on both alleles results in a Dravet syndrome phenotype which is more severe than average. This first report of a de novo homozygous variant in the SCN1A gene, therefore, provides a clear illustration of a complex genotype-phenotype relationship.